Chemokines and ‘bath salts’: CXCR4 receptor antagonist reduces rewarding and locomotor-stimulant effects of the designer cathinone MDPV in rats

Oliver, Chicora F.; Simmons, Steven J.; Nayak, Sunil U.; Smith, Garry R.; Reitz, Allen B.; Rawls, Scott M.

doi:10.1016/j.drugalcdep.2018.01.013

Cited by 21 publications

(13 citation statements)

References 27 publications

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“…However, no such effect was observed for 4-CMC used at both doses that produced significant increases of locomotor activity during 120 min. Results of our study demonstrating that 4-MeO-PVP produces CPP in mice are in line with findings showing that other synthetic cathinones, e.g., MDPV-highly selective for DAT (Eshleman et al 2013), evoke similar effects in both rats (Atehortua-Martinez et al 2019;Gregg et al 2016;King et al 2015;Oliver et al 2018) and mice (Karlsson et al 2014). The place preference behavior was also induced by other pyrrolidinecontaining cathinones, i.e., α-PVT, α-PVP, α-PBP (Cheong et al 2017;Gatch et al 2015).…”

Section: Discussionsupporting

confidence: 91%

Behavioral Effects of 4-CMC and 4-MeO-PVP in DBA/2J Mice After Acute and Intermittent Administration and Following Withdrawal from Intermittent 14-Day Treatment

2021

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Synthetic cathinones appeared on the market in the 2000s as new psychoactive substances and gained significant prevalence among drug abusers. Cathinones produce psychostimulant and empathogenic effects by enhancing dopaminergic, noradrenergic, and serotoninergic neurotransmission in the brain, and those which potently and selectively enhance dopaminergic transmission are considered to have higher abuse potential. The present study examines the behavioral effects related to psychostimulant properties, abuse potential, and addiction in DBA/2J mice of two cathinones with different profile of action on monoamine system, 4-chloromethcathinone (4-CMC), and 4-methoxy-pyrrolidinopentiophenone (4-MeO-PVP). 4-CMC and 4-MeO-PVP increase spontaneous locomotor activity after acute treatment and produce behavioral sensitization after 7-day intermittent treatment, which is a common feature of drugs of abuse. 4-MeO-PVP, but not 4-CMC, produces conditioned place preference after 4 days, indicating its rewarding properties. Finally, the ability of 4-CMC and 4-MeO-PVP to induce withdrawal symptoms after discontinuation from 14-day treatment was assessed using a battery of tests for behavioral markers of depression in mice: a tail suspension test, a forced swim test, measuring despair, and a sucrose preference test, measuring anhedonia. None of the three tests revealed increased depressive symptoms. Moreover, neither spontaneous locomotor activity nor motor performance on a rotarod was impaired after 14-day treatment with the tested compounds. These results indicate that 14-day treatment of mice with 4-CMC or 4-MeO-PVP does not induce significant withdrawal symptoms after cessation, nor significant impairment of dopaminergic circuitry resulting in motor impairment. The current study shows that 4-CMC and 4-MeO-PVP produce abuse-related behavioral changes in mice, which are more pronounced after more dopamine-selective 4-MeO-PVP.

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Section: Discussionsupporting

confidence: 91%

Behavioral Effects of 4-CMC and 4-MeO-PVP in DBA/2J Mice After Acute and Intermittent Administration and Following Withdrawal from Intermittent 14-Day Treatment

2021

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“…There is some evidence for an ability of MDPV to down-regulate expression of the glutamate transporter GLT-1 (Gregg et al 2016), which is responsible for clearance of the majority of extracellular glutamate, and as a result this down-regulation of GLT-1 raises extracellular glutamate levels, potentially leading to excitotoxicity. In addition, some of the behavioral effects of MDPV (reward and hyperlocomotion) have been shown to be attenuated by antagonism of CXC4R chemokine receptors (Oliver et al 2018). However, as will be detailed later in this review, it is still unclear if any of these non-monoaminergic mechanisms of action contribute to the ability of synthetic cathinones to induce lasting cognitive dysfunction, neurotoxicity and neuroinflammation.…”

Section: Overview Of Synthetic Cathinonesmentioning

confidence: 99%

“…This is not to assert that synthetic cathinones do not induce neuroinflammation; rather, it is a phenomenon that has not yet been investigated, likely a result of the relative infancy of synthetic cathinone research. Indeed, one recent study demonstrated attenuation of MDPV-induced reward and hyperlocomotion by a CXCR4 chemokine receptor antagonist (Oliver et al 2018), providing one of the first glimpses of evidence for neuroimmune crosstalk in the central actions of synthetic cathinones. Thus, avenues of future research should include detailed analyses of the myriad of quantifiable mechanisms and processes of neuroinflammation that are potentially activated by synthetic cathinones.…”

Section: Do Synthetic Cathinones Induce Neuroinflammation?mentioning

confidence: 99%

Cognitive deficits and neurotoxicity induced by synthetic cathinones: is there a role for neuroinflammation?

Leyrer‐Jackson

Nagy

2018

Psychopharmacology

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Rationale.-The number of synthetic derivatives of cathinone, the primary psychoactive alkaloid found in Catha edulis (khat), has risen exponentially in the past decade. Synthetic cathinones (frequently referred to as "bath salts") produce adverse cognitive and behavioral sequelae, share similar pharmacological mechanisms of action with traditional psychostimulants, and may therefore trigger similar cellular events that give rise to neuroinflammation and neurotoxicity Objectives.-In this review, we provide a brief overview of synthetic cathinones, followed by a summary of cognitive deficits in animals and humans that have been documented following acute or repeated exposure. We also summarize growing evidence from in vitro and in vivo studies for synthetic cathinone-induced neurotoxicity, and provide a working hypothetic model of potential cellular mechanisms. Results.-Synthetic cathinones produce varying effects on markers of monoaminergic terminal function, and can increase the formation of reactive oxygen and nitrogen species, induce apoptotic signaling, and cause neurodegeneration and cytotoxicity. We hypothesize that these effects result from biochemical events similar to those induced by traditional psychostimulants. However, empirical evidence for the ability of synthetic cathinones to induce neuroinflammatory processes is currently lacking. Conclusions.-Like their traditional psychostimulant counterparts, synthetic cathinones appear to induce neurocognitive dysfunction and cytotoxicity, which are dependent on drug type, dose, frequency, and time following exposure. However, additional studies on synthetic cathinoneinduced neuroinflammation are clearly needed, as are investigations into the neurochemical and neuroimmune mechanisms underlying their neurotoxic effects. Such endeavors may lead to novel therapeutic avenues to promote recovery in habitual synthetic cathinone users.

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“…CXCL12 injected into the substantia nigra enhances extracellular dopamine in the dorsal striatum in a CXCR4 receptor-dependent manner [ 120 , 279 ]. More recently, CXCR4 antagonism by AMD3100 was shown to reduce cocaine conditioned place preference and locomotor activation [ 165 ], and similar effects were observed for AMD3100 against MDPV [ 239 ]. At the cellular level, both cocaine and MDPV enhance CXCL12 gene expression in the mesolimbic circuit [ 165 , 239 ].…”

Section: Targeting Neuroimmune and Glutamate Signaling For Pharmacothmentioning

confidence: 77%

Interactions of neuroimmune signaling and glutamate plasticity in addiction

Gipson

Rawls

Scofield

et al. 2021

J Neuroinflammation

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Chronic use of drugs of abuse affects neuroimmune signaling; however, there are still many open questions regarding the interactions between neuroimmune mechanisms and substance use disorders (SUDs). Further, chronic use of drugs of abuse can induce glutamatergic changes in the brain, but the relationship between the glutamate system and neuroimmune signaling in addiction is not well understood. Therefore, the purpose of this review is to bring into focus the role of neuroimmune signaling and its interactions with the glutamate system following chronic drug use, and how this may guide pharmacotherapeutic treatment strategies for SUDs. In this review, we first describe neuroimmune mechanisms that may be linked to aberrant glutamate signaling in addiction. We focus specifically on the nuclear factor-kappa B (NF-κB) pathway, a potentially important neuroimmune mechanism that may be a key player in driving drug-seeking behavior. We highlight the importance of astroglial-microglial crosstalk, and how this interacts with known glutamatergic dysregulations in addiction. Then, we describe the importance of studying non-neuronal cells with unprecedented precision because understanding structure-function relationships in these cells is critical in understanding their role in addiction neurobiology. Here we propose a working model of neuroimmune-glutamate interactions that underlie drug use motivation, which we argue may aid strategies for small molecule drug development to treat substance use disorders. Together, the synthesis of this review shows that interactions between glutamate and neuroimmune signaling may play an important and understudied role in addiction processes and may be critical in developing more efficacious pharmacotherapies to treat SUDs.

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Chemokines and ‘bath salts’: CXCR4 receptor antagonist reduces rewarding and locomotor-stimulant effects of the designer cathinone MDPV in rats

Abstract: A CXCR4 antagonist reduced the rewarding and locomotor-activating effects of MDPV. Our results identify the existence of chemokine/cathinone interactions and suggest the rewarding and stimulant effects of MDPV, similar to cocaine, require an active CXCL12/CXCR4 system.

Cited by 21 publications

References 27 publications

Behavioral Effects of 4-CMC and 4-MeO-PVP in DBA/2J Mice After Acute and Intermittent Administration and Following Withdrawal from Intermittent 14-Day Treatment

Behavioral Effects of 4-CMC and 4-MeO-PVP in DBA/2J Mice After Acute and Intermittent Administration and Following Withdrawal from Intermittent 14-Day Treatment

Cognitive deficits and neurotoxicity induced by synthetic cathinones: is there a role for neuroinflammation?

Interactions of neuroimmune signaling and glutamate plasticity in addiction

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